Skip to content

118

    Issue Date: January 2024

    Maternal Brain Circuit Activated by Pups’ Cries Boosts Oxytocin

    • Infants’ cries drive an increase in brain levels of oxytocin, a hormone that induces contractions during labor and regulates maternal behaviors and milk production.
    • Oxytocin is produced by neurons in a brain area called the hypothalamus, but researchers did not know how infants’ distress sounds could increase its levels.  
    • A new mouse study has identified a circuit, present only in the maternal brain, that responds to the sound of infant cries and that regulates maternal behaviors such as taking care of pups.

    A crying infant might pull on the heartstrings of any passerby, but those tears have a well-known physiological effect on the baby’s mother. By somehow increasing levels of the hormone oxytocin, the sound of a baby wailing compels a new mom to provide care for the baby and sometimes to release breast milk

    Researchers have now identified the mechanism underlying the link between infants’ cries and oxytocin increase  (1). In mice, they discovered a neuronal circuit that exists exclusively in the brains of mothers and activates oxytocin-releasing neurons in a brain region called the hypothalamus. They found that this circuit engages the auditory system and was activated by the sounds of a pup’s distress call. The findings show how sensory cues produced by an infant can spark a neural chain of events in the maternal brain to directly increase oxytocin levels.

    “We found that infant cries could stimulate oxytocin neurons and lead to oxytocin release,” says Robert Froemke, a neuroscientist at New York University who co-led the study. “However, this required seconds to minutes of hearing the cries, as the oxytocin neurons are slow to respond, only firing after hearing quite a few cries over and over again, and when ‘they are sure’ there’s really a needy baby nearby.”

    Oxytocin is a peptide hormone that is produced mainly in a specific nucleus of the hypothalamus, called the paraventricular nucleus (PVN). Its main functions include inducing contractions during labor, stimulating the release of breast milk, and promoting parental care (2). To investigate how exactly a baby’s cries act as a signal for neurons in the PVN to release oxytocin, the researchers began by recording the activity of those neurons in mouse dams while playing auditory recordings of pups’ distress calls. The neurons got activated, the researchers found but only after pup distress calls had been broadcast for about 30 minutes. Those neurons didn’t get activated when the researchers played other sounds—and they also did not get activated in mice that had never had babies.  

    Next, the researchers injected the PVN neurons with a virus-based tracer molecule to identify what other parts of the brain they connected with. The tracer revealed that the neurons projecting from the PVN come from a lower brain area called the thalamus—and specifically, a part of the thalamus that processes auditory input. Recording showed that the extended thalamic stimulation spurred oxytocin production by lifting the inhibition on PVN neurons. Other studies have hinted that the thalamic region involved plays a role in perceiving unconscious sounds, especially ones that carry emotional value. 

    To demonstrate this circuit’s involvement in parental behaviors relating to caring for infants, Froemke and his colleagues used a technique called chemogenetic suppression to prevent the thalamic neurons from signaling to the PVN. Those dams eventually stopped retrieving crying pups that had been moved away from them by researchers. But when the chemical block was removed, their commitment to pup retrieval returned. Finally, by labeling oxytocin molecules with sensors, the researchers also showed that activation of the PVN neurons upon hearing pups’ distress cries resulted in oxytocin being released specifically in a brain area that has been linked to maternal behaviors (3). That brain area, called the ventral tegmental area, is thought to regulate behavior related to reward and motivation. 

    According to a commentary accompanying the study, one of its limitations was the unnatural conditions of the experiment, with mice hearing recordings of pup calls (4). The circuitry may be different if the dams hear their own pups’ cries, say the commentary’s authors, Flavia Ricciardi and Cristina Márquez from the University of Coimbra in Portugal. One question the research raises is whether this circuitry is affected in people with conditions such as postpartum depression, they write.  

    Froemke says a future direction is to study how this circuit affects oxytocin’s role in lactation and nursing. “We’re hopeful that new technical developments will let us start working on bona fide milk delivery in years ahead,” he says. 

    References

      1. Valtcheva S, Issa HA, Bair-Marshall CJ, Martin KA, Jung K, Zhang Y, Kwon HB, Froemke RC. Neural circuitry for maternal oxytocin release induced by infant cries. Nature. 2023: 621(7980):788-795.
      2. Valtcheva S, Froemke RC. Neuromodulation of maternal circuits by oxytocin. Cell Tissue Res. 2019: 375(1):57-68. 
      3. Pedersen CA, Caldwell JD, Walker C, Ayers G, Mason GA. Oxytocin activates the postpartum onset of rat maternal behavior in the ventral tegmental and medial preoptic areas. Behav Neurosci. 1994: 108(6):1163-1171. 
      4. Ricciardi F, Márquez C. The neural circuit that makes maternal mice respond to pups’ cries. Nature. 2023: 621(7980):693-694.

    Human Milk Sugars Help Reduce Infections That Cause Preterm Births

    • Group B Streptococcus (GBS) infections are a major cause of preterm births.
    • Sugars found in human milk, called human milk oligosaccharides (HMOs), were found to inhibit GBS infection and reduce inflammation in mice and human tissues.
    • HMOs could thus have potential therapeutic applications against GBS infections in humans and could help reduce preterm births.

    Preterm births are a major global problem, affecting approximately 11.1% of all pregnancies worldwide and nearly 10% of all pregnancies in the United States (1). Microbial infections are a major cause of preterm births, and are responsible for 40% of preterm births in the United States. Bacterial infections can lead to an inflammatory response that can then cause premature onset of labor. Streptococcus agalactiae or Group B Streptococcus (GBS) is one of the most common pathogens responsible for such infections.

    GBS is a commensal bacterium often found in the human gastrointestinal and reproductive tracts. It can cause opportunistic infections that lead to adverse pregnancy outcomes such as preterm birth and stillbirth, making it a leading cause of infant morbidity and mortality (2-6). “I wanted to know the drivers of preterm birth, and one of the biggest ones when you look at the bacterial pathogens that cause preterm birth is Group B Strep,” says Jennifer Gaddy, Associate Professor of medicine at Vanderbilt University Medical Center.

    A recent study led by Gaddy and Steve Townsend, Professor of Chemistry at Vanderbilt University, found that sugars found in human milk, known as human milk oligosaccharides (HMOs), can inhibit GBS infection and reduce inflammation in mice and human tissues (7). HMOs could thus have potential therapeutic applications against GBS infections and could help reduce preterm births.

    From chemistry to biology

    Townsend has long been working on studying and synthesizing HMOs, and reached out to Gaddy to investigate their biology. “That launched an almost 10-year collaboration now where he’s done the chemistry and I’ve done the biology,” says Gaddy. “Breast milk has all these wonderful molecules in it, and I was really interested in what molecules have antimicrobial or immunomodulatory activity, so this paper is really a culmination of almost a decade of work,” she says.

    Pregnant women are routinely screened for GBS and given antibiotics if they are found to have the bacteria. “But this does not prevent preterm birth or preterm rupture of membranes, because usually the mother is not screened until late in the third trimester, so we were really looking at being able to prevent or clear these earlier infections,” says Rebecca Moore, first author of the new paper (7) (see previous article). Moore conducted the work as a postdoctoral student with Gaddy and was previously a PhD student with Townsend. The researchers decided to test whether HMOs could serve as an alternative way to control GBS infections.

    HMOs are a group of sugars present only in human milk, and have been shown to function as prebiotics, anti-adhesive antimicrobials, and immunomodulators in the infant gut (8-11) (see previou article) “HMOs act as anti-adhesives, so they help prevent the adhesion of bacteria, and they can act as prebiotics, so they help increase the good bacteria,” says Moore. GBS pathogenesis depends on the bacteria’s ability to adhere to and colonize the host tissues, so the researchers tested how HMOs affected this ability.

    The researchers investigated the effects of a heterogeneous mixture of HMOs isolated from human milk on GBS infection in a pregnant mouse model. “We can take a pregnant mouse, and then just pipette bacteria into the vagina, and those bacteria ascend through the cervix up into the uterus, they cross the placenta, they infect the fetus, we get rupture of membranes, we get inflammation, we get preterm birth, we get fetal demise, we even get maternal demise, just like you get in the clinical model, so this is a really powerful model,” says Gaddy. “We’re marching towards trying to get closer to modeling what happens in a human being,” she says. 

    Examining HMOs in human tissues and mice

    The researchers’ mouse experiments involved a lot of hard work, with multiple people working 11-hour days. “It’s all hands on deck,” says Gaddy. But the hard work paid off.

    “Very excitingly, we found that when we fed the mice HMOs orally or gave them HMOs vaginally, they were able to significantly reduce the bacterial burden of Group B Strep in all of the reproductive organs,” says Moore. HMOs also reduced inflammation in the reproductive tissues and fetal compartments of GBS-infected mice compared with infected mice not given HMOs.

    The orally-delivered HMOs did not reduce bacterial burden as much as when they were delivered vaginally, but the fact that they had an effect at all came as a surprise. Gaddy says Moore was the one who suggested trying the HMOs orally in order to test whether they could eventually be given as orally-ingested pills to humans. “I said, ‘I don’t think it’ll work, but let’s do it’, and I was really shocked that it actually was very efficacious orally, and we are now in the process of trying to figure out how that works by tagging the HMOs and following them when we deliver them in vivo,” says Gaddy. She suggests that one of the ways HMOs might be working when delivered orally is through their effects on the immune system.

    In addition to seeing whether HMOs could reduce bacterial burden, the researchers also examined their effects on preventing preterm births in the pregnant mouse model. Pregnant mice infected with GBS experience both preterm birth and maternal death, as well as elevated levels of inflammatory cytokines. “We saw no instances of maternal death or preterm birth when the mice were given the HMOs, so that was exciting,” says Moore. “We also saw that immunologically HMOs also reduced the cytokines that are related to preterm birth in the mouse model,” she says.

    In addition to the mouse model, the researchers also used gestational membranes from a human placenta and a human vaginal organoid tissue model. “We’re always trying to use these complementary techniques because although the mouse immune system is very similar to ours, there are salient differences between the mouse and human reproductive tract and placenta,” says Gaddy. 

    “Looking at the vaginal organoids, we wanted to see if HMOs were able to inhibit adherence to this tissue, because if we’re able to inhibit that initial adherence we can prevent the ascending infection to the baby,” says Moore. “We found that the HMOs were able to prevent bacterial adherence to these tissues as well,” she says. They also prevented the bacteria from forming biofilms.

    HMOs also played a role in decreasing inflammation. “These compounds were really potent anti-inflammatory compounds,” says Gaddy. She suggests that HMOs could be useful against a variety of infections and inflammatory diseases. “I think that these molecules might have really potent, broad, anti-inflammatory applications,” she says.

    Fulfilling HMOs’ potential to prevent preterm births

    The study concludes that HMOs reduce GBS infection in a mouse model, reduce GBS adherence in an organoid model, and decrease reproductive tissue inflammation and the production of proinflammatory cytokines (7). “If you can deploy a molecule that has both antimicrobial activity and anti-inflammatory activity, there are some potent applications for that,” says Gaddy.

    The researchers suggest that their findings highlight the potential of HMOs to reduce GBS infection and thus prevent preterm births. “The thought process is that HMOs could be given to the mother almost like a vitamin that she would take during pregnancy,” says Moore.

    As antibiotic resistance becomes more of a problem, HMOs might serve as a safe alternative to antibiotics. “Most people get exposed to these molecules at least once in their life, and that should underscore their safety and their efficacy,” says Gaddy.

    “These are natural products that are present in human milk, which is a source of nutrition that 70% of people have had in their lifetime, so they have utility because of the public trust in them,” she says. 

    However, more studies are needed before HMOs could be used in humans. The current study used a heterogeneous mixture of HMOs, and Gaddy says the next step is to narrow down the specific properties of different sugars or combinations of sugars. “We’re trying to ascertain from the 11 dominant sugars that we’re seeing in the HMO cocktail, which ones are doing the antimicrobial activity, which ones are doing the anti-biofilm activity, which ones are expanding commensals, which ones are modulating the immune system, and we’re in the process right now of teasing that out,” says Gaddy.

    The researchers are aiming to synthesize individual HMO molecules and then test their effects in their existing models. “I think we’ll probably spend the next five years doing that, and then after we know which molecules do what, it’ll be easier for us to move into a human clinical trial,” says Gaddy.

    But finding the right sugars or combination of sugars will take some effort, highlighting the complexity of human milk. “One of the first steps is being able to synthetically produce these HMOs in the right combination, and we haven’t found a combination that works as well as the combination that is found naturally in breast milk,” says Moore. “There are over 200 HMOs, so it’s a matter of finding that sweet spot,” she says.

    References

    1. Blencowe H, Cousens S, Chou D, Oestergaard M, Say L, Moller AB, Kinney M, Lawn J; Born Too Soon Preterm Birth Action Group. Born too soon: the global epidemiology of 15 million preterm births. Reprod Health. 2013;10 Suppl 1(Suppl 1):S2.
    2. Dai, W.; Zhang, Y.; Xu, Y.; Zhu, M.; Rong, X.; Zhong, Q. The effect of group B Streptococcus on maternal and infants’ prognosis in Guizhou, China. Biosci. Rep. 2019, 39 (12).
    3. Bianchi-Jassir F, Seale AC, Kohli-Lynch M, Lawn JE, Baker CJ, Bartlett L, Cutland C, Gravett MG, Heath PT, Ip M, Le Doare K, Madhi SA, Saha SK, Schrag S, Sobanjo-Ter Meulen A, Vekemans J, Rubens CE. Preterm birth associated with group B Streptococcus maternal colonization worldwide: Systematic review and meta-analyses. Clin Infect Dis. 2017 Nov 6;65(suppl_2):S133-42.
    4. Nan C, Dangor Z, Cutland CL, Edwards MS, Madhi SA, Cunnington MC. Maternal group B Streptococcus-related stillbirth: a systematic review. BJOG. 2015 Oct;122(11):1437-45.
    5. Sass L. Group B streptococcal infections. Pediatr Rev. 2012 May;33(5):219-24.
    6. Verani JR, McGee L, Schrag SJ; Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention (CDC). Prevention of perinatal group B streptococcal disease–revised guidelines from CDC, 2010. MMWR Recomm Rep. 2010 Nov 19;59(RR-10):1-36.
    7. Moore RE, Spicer SK, Lu J, Chambers SA, Noble KN, Lochner J, Christofferson RC, Vasco KA, Manning SD, Townsend SD, Gaddy JA. The utility of human milk oligosaccharides against Group B Streptococcus infections of reproductive tissues and cognate adverse pregnancy outcomes. ACS Cent Sci. 2023 Aug 9;9(9):1737-49.
    8. Morrow AL, Ruiz-Palacios GM, Jiang X, Newburg DS. Human-milk glycans that inhibit pathogen binding protect breast-feeding infants against infectious diarrhea. J Nutr. 2005 May;135(5):1304-7.
    9. Chichlowski M, De Lartigue G, German JB, Raybould HE, Mills DA. Bifidobacteria isolated from infants and cultured on human milk oligosaccharides affect intestinal epithelial function. J Pediatr Gastroenterol Nutr. 2012 Sep;55(3):321-7.
    10. Zivkovic AM, German JB, Lebrilla CB, Mills DA. Human milk glycobiome and its impact on the infant gastrointestinal microbiota. Proc Natl Acad Sci U S A. 2011 Mar 15;108 Suppl 1(Suppl 1):4653-8. 
    11. Newburg DS, Grave G. Recent advances in human milk glycobiology. Pediatr Res. 2014 May;75(5):675-9.

     

    Contributed by

    Dr. Sandeep Ravindran

    Freelance Science Writer

    Sandeepr.com

    Drinking Milk Is Linked to Lower Fracture Risk in Women

    • Analysis of data extracted from the Nurses Health Study that began in 1980 revealed that total dairy intake was linked to a lower risk of fractures in middle-aged and older women.
    • Consuming milk, yogurt, and cheese was correlated with a lower risk of fragility fractures of the hip. 
    • The protective effects of dairy could benefit women both before and after menopause.

    For many people, aging increases their risk of a fracture from a slip or fall from standing height or even more minor injuries. These injuries usually reveal the underlying condition of osteoporosis, characterized by low bone mineral density and a loss of the micro-architecture of bone tissue. Approximately 1.5 million new cases of fragility fractures are diagnosed annually in the U.S. alone [1]. Although older women are considered most at risk of these injuries, a recent analysis revealed that the risk of fragility fractures begins to increase when women are in their forties [2]. 

    Dairy consumption is thought to improve bone mineral density because foods such as milk and cheese are rich in calcium, phosphorus, and other minerals important for bone health. Despite this connection, the correlation between a dairy-rich diet and fracture risk has been tenuous. A 2018 study reported that an extra daily serving of dairy, at least half of which was milk, was linked to a 6 percent decrease in risk of hip fracture amongst postmenopausal women in the Nurses’ Health Study (NHS) [3]. But some other studies have found no correlation between dairy consumption and hip fracture risk [4], while others have found that drinking milk can reduce these fractures.  

    In a new study, researchers led by Lynn Moore of the Boston University Chobanian & Avedisian School of Medicine set out to better understand whether dairy consumption could protect bone health in middle-aged and older women [2]. The researchers turned to data from a large cohort of women included in the NHS, a study that tracked the health of female nurses starting in 1980. The researchers homed in on data for approximately 103,000 participants in the study. They excluded participants with a history of osteoporosis, previous fragility fractures, and those with missing information on dairy intake.  

    The team also examined participants’ exercise habits, medical history, and nutrition information collected in food frequency questionnaires that were sent to the study participants every few years. They included milk, cheese, and yogurt in their definition of dairy but left out butter, cream cheese, and cream because of the scant amounts of calcium present in these foods. Over the 24-year period of available data, there were a total of 5494 fractures across the participants. 

    In their analyses, funded in part by the National Dairy Council, the researchers discovered that women who consumed 2 or more daily servings of dairy—and milk in particular—had experienced fewer fractures than those who consumed the lowest amounts of dairy. Women who consumed more than 1 serving of cheese each day also had lower rates of fractures compared with those who ate less than 1 serving of cheese weekly. But the researchers found no correlation between eating yogurt and reduced fracture risk. Overall, dairy consumption appeared to benefit women who were postmenopausal as well as those who were under the age of 65.

    The protective effects of dairy did not seem to be a result of the diet’s calcium content alone, because calcium from non-dairy sources was not correlated with a lower risk of fracture. The bone boost linked to dairy appeared independent of women’s consumption of calcium, vitamin D, or protein from non-dairy foods in their diet. 

    The inconclusive results of earlier studies may have stemmed from variations in the kinds of dairy consumed in different parts of the world, the authors suggest. For instance, their analysis of women in the U.S. found no link between yogurt and bone health, but yogurt consumption in this cohort [2] was much lower than their consumption of milk and cheese. Another reason for the variability amongst studies could be the quality of dairy. For example, a recent meta-analysis of studies conducted in 14 cohorts suggested that in the U.S., one extra serving of milk each day reduced the risk of hip fractures by 7 percent, but this correlation did not exist in studies of Scandinavian populations—perhaps because milk in the U.S. is often fortified with vitamin D [5]. 

    Although the current study [2] is one of the largest of its kind, the authors noted that since nurses are likely to be more health-aware and practice healthy behaviors, there may have been other unmeasured preventive actions that contributed to the observed links between dairy and bone health. Future studies should aim to analyze whether high-fat and low-fat dairy products confer different protective effects, they suggested in their discussion of the results. Nonetheless, they concluded that the present data to a protective effect of milk and dairy products against fragility fractures in women. They concluded in their study that “this finding may provide middle-aged and older females with one of a series of methods for preventing future fractures.” 

    References

    1. Clynes MA, Harvey NC, Curtis EM, Fuggle NR, Dennison EM, Cooper C. The epidemiology of osteoporosis. British Medical Bulletin. 2020 Mar;133(1):105-17.
    2. Yuan M, Hu FB, Li Y, Cabral HJ, Das SK, Deeney JT, Zhou X, Paik JM, Moore LL. Types of dairy foods and risk of fragility fracture in the prospective Nurses’ Health Study cohort. The American Journal of Clinical Nutrition. 2023 Dec;118(6):1172-81. 
    3. Feskanich D, Meyer HE, Fung TT, Bischoff-Ferrari HA, Willett WC. Milk and other dairy foods and risk of hip fracture in men and women. Osteoporosis International. 2018 Feb; 29:385-96.
    4. Benetou V, Orfanos P, Zylis D, Sieri S, Contiero P, Tumino R, Giurdanella MC, Peeters PH, Linseisen J, Nieters A, Boeing H. Diet and hip fractures among elderly Europeans in the EPIC cohort. European journal of clinical nutrition. 2011 Jan;65(1):132-9.
    5. Hidayat K, Du X, Shi BM, Qin LQ. Systematic review and meta-analysis of the association between dairy consumption and the risk of hip fracture: critical interpretation of the currently available evidence. Osteoporosis International. 2020 Aug; 31:1411-25.

    Molecular Mechanisms of Milk Production Reveal an Evolutionary Back-up Plan

    • To understand the influence of the Rankl protein on lactation, researchers turned off cellular receptors for Rankl in two types of cells within a mouse mammary gland.
    • Receptor loss in basal cells did not affect lactation performance, but receptor loss in luminal cells led to lactation failure for the first litter.
    • Mice with receptor loss on luminal cells were able to successfully lactate with their second and third litters due to novel finding that basal stem cells could produce Rank-positive luminal cells.

    If you have ever wondered what one teaspoon of baking soda does for an entire batch of cookies, omit this ingredient the next time you bake, and your flat cookies will clue you in. Biologists actually use the “omit one ingredient” approach when trying to understand the function of a gene or protein in an organism. Sometimes the best way to figure out what something does is to take it away and see what happens. 

    In a new study [1], a team of Spanish researchers applied this method to understand how one protein affects milk production by the mammary gland [1]. The protein of interest is called Rankl (Receptor Activator of Nuclear factor-Kappa beta Ligand). The research team knew that the expression of Rankl within the mammary gland was necessary for proper mammary gland development and milk production based on previous animal studies that turned off Rankl signaling in all cells. Hoping to zoom in on the specific impact of this protein on lactation, the Spanish team turned off the Rankl signaling pathway in just two cellular lineages.

    The team focused on luminal cells and basal cells, the two types of mammary epithelial cells [1]. During embryonic development, basal stem cells give rise to luminal and basal cell lines. During puberty, these cell types are still in their progenitor phase and have yet to differentiate or specialize. However, by the onset of lactation, luminal cells give rise to alveolar and ductal cells (milk secreting cells), whereas basal cells differentiate into myoepithelial cells (which are involved in milk ejection) [2, 3]. 

    Using a mouse model, the researchers blocked the signal from the Rankl protein by genetically removing (aka “knocking out”) the instructions for making the Rankl cell surface receptor on either luminal or basal cells. Then, they compared tissue development and lactation performance between mice with basal Rank receptor loss, mice with luminal Rank receptor loss, and control mice (no genetic interventions). 

    Mice with basal Rank receptor loss did not exhibit developmental changes or issues with lactation performance over multiple pregnancies. The loss of basal Rankl signaling did not appear to impact the ability of basal cells to differentiate over the course of the female mouse’s reproductive lifespan or the function of the mammary gland during pregnancy or lactation [1]. Rankl protein, it seems, was not integral to basal cell function.

    In contrast, the team found that mice with luminal Rank receptor loss had fewer luminal progenitor cells during puberty compared with control mice. During pregnancy, they observed an impaired response of luminal cells to the hormones progesterone and prolactin, which led to abnormal differentiation of alveolar cells [1]. These aberrant alveolar cells were unable to secrete milk, resulting in lactation failure.

    If the research study ended there, it would be interesting and scientifically valuable—the research team was able to establish that Rankl proteins are required for successful lactation because of their influence on luminal cell progenitor populations and luminal cell differentiation into alveolar cells [1]. But the researchers decided to follow their knockout mice through multiple pregnancies and, in doing so, were able to make an even more ground-breaking finding. 

    To the researchers’ surprise, luminal rank loss mice who couldn’t produce milk for their first litter were able to do so for all the pups in their second litter and most pups in their third litter [1]. Unlike the first pregnancy, alveolar cell development was normal during the second and third pregnancy, resulting in what the researchers describe as “an almost normal lactating gland” [1]. What had happened between the first and second pregnancies to bring about this functional change? Amazingly, Rank-deleted luminal cells had been replaced during the second pregnancy by Rank-positive cells [1]. And even more remarkable, the cellular grandparent of these functional luminal cells were basal cells. 

    Basal cells in the mammary epithelium were known to be bipotent—able to produce two cell types—during embryonic development but not in adulthood. The researchers hypothesize that in their mouse model, basal cell bipotency was triggered by molecular changes brought about by lactation failure specifically in the context of luminal Rank loss [1]. Exactly which molecular changes trigger basal cells to come to the functional rescue of the abnormal luminal cells is still unknown, but the study authors hypothesize it was the combination of inflammatory signals generated by the Rank-deleted luminal progenitors and/or the abnormal alveolar cells they produced and an excess of Rankl protein, the result of fewer receptors for Rankl protein binding [1]. 

    It is tempting to propose that the triggering of basal cell bipotency is an evolved mechanism to protect lactation in mice, and potentially in other mammals (even humans). If normal alveolar cell development is indeed critical to successful lactation, having a back-up plan to prevent lactation failure in second pregnancies and beyond would ensure reproductive success across mammals. 

    References

    1. Rocha AS, Collado-Solé A, Graña-Castro O, Redondo-Pedraza J, Soria-Alcaide G, Cordero A, Santamaría PG, González-Suárez E. Luminal Rank loss decreases cell fitness leading to basal cell bipotency in parous mammary glands. Nature Communications. 2023 Oct 9;14(1): 6213.
    2. Tiede B, Kang Y. From milk to malignancy: the role of mammary stem cells in development, pregnancy and breast cancer. Cell Research. 2011 Feb;21(2): 245-57.
    3. Cristea S, Polyak K. Dissecting the mammary gland one cell at a time. Nature Communications. 2018 Jun 26;9(1): 2473.

    Back to SPLASH!® Home